Photodynamic therapy (PDT) has developed into a new treatment for tumors since earlier 1980s. Its principle is to irradiate a focus (tumor) tissue into which a photosensitizer has been injected by laser of special wavelength. Elemental oxygen (O2) existing in the tissue is excited by the photosensitizer to produce a reactive oxygen species (ROS), such as singlet oxygen (1O2). Thus, apoptosis or necrosis of tumor cells occurs and the tumor is treated. So called special wavelength means the largest absorption wavelength of the photosensitizer in the red region (>600 nm). PDT just specifically irradiates tumor tissues and selectively damages tumor cells, but with little or no damage to normal tissues or organs. It is a non invasive therapy for human body, with little side effect (no trauma and pains due to surgery, no emesis, nausea and immunosuppression due to radiotherapy and chemotherapy), and it can be used alone or combined with other therapies for many times.
Light, oxygen in tissues and photosensitizers are three main factors for PDT. Further, photosensitizers play a key role. The first generation of porphyrin photosensitizer, such as porfimer sodium is successfully used in tumor treatment in clinic, and a significant effect is achieved. However, there are some obvious defects, 1) a short of absorption wavelength (630 nm) in the red region causes the wavelength and matched laser cannot penetrate enough depth to skill tumor and a small molar absorption coefficient (ϵ). Thus, photoactive activity is lower. 2) They are mixture of multicomponent porphyrin. 3) The elimination rate in vivo is slow and the retentive phototoxicity is large. After receiving the treatment, the patient needs to be protected from the light for 4-8 weeks. The patient feels great psychological pain. Therefore, since later 1990s, researchers have stated the studies on the second generation of photosensitizers represented by chlorin photosensitizers, such as benzoporphyrin derivatives (BPD), chlorophyll a degradation derivatives and bacteriochlorin. Since the structure of chlorins photosensitizer is clear and simple, the biggest absorption wavelength in the red region (>600 nm) is changed to 660-690 nm compared with the first generation of porphyrins photosensitizer, the laser of this wavelength possesses the best depth for tumor skilling. Further the molar absorption coefficient (ϵ) of chlorins photosensitizer is higher than that of the first generation of porphyrins photosensitizer by one order of magnitude. The photoactive activity is strong, the metabolism in body is fast, and the retentive phototoxicity is small. It has been a hotspot in the research for new photosensitizers. The report regarding chlorins photosensitizer is increasing (for example, zhu guohua et. al., Synthetic process fro 132-N-(2-hydroxyethyl)-153-N-(2-hydroxyethyl)-173-methoxycarbonyl chlorin e6-131,152-diamide and studies on optical property. Chemical Engineer, 2015, 235(4): 1-5; Fang ying, et al., The degradation of silkworm feces chlorophyll and Synthesis of chlorin e6 ether derivatives. organic chemistry, 1995, 15(5): 493-498; Xiuhan Guo, et al. Synthesis of new chlorin derivatives containing maleimide functional group and their photodynamic activity evaluation. Bioorganic & Medicinal Chemistry Letters, 2015, 25(19): 4078-4081; Gushchina, O. I., et al. Synthesis of amide derivatives of chlorine e6 and investigation of their biological activity. Journal of Photochemistry and Photobiology B: Biology, 2015, 153: 76-81; Kwitniewski, M., et al. Diamino acid derivatives of PpIX as potential photosensitizers for photodynamic therapy of squamous cell carcinoma and prostate cancer: in vitro studies. Journal of Photochemistry and Photobiology B: Biology, 2009, 94, 214-222; Serra, V. V., New porphyrin amino acid conjugates: synthesis and photodynamic effect in human epithelial cells. Bioorganic & Medicinal Chemistry, 2010, 18, 6170-6178; Wang, H. M., Porphyrin with amino acid moieties: a tumor photosensitizer. Chem. Biol. Interact. 2008, 172, 154-158; Smith, K. M., et al. Syntheses and cellular investigations of 173-, 152-, and 131-amino acid derivatives of chlorin e6. Journal of Medicinal Chemistry, 2011, 54: 7464-7476; Yao jianzong, et al., Synthesis and photosensitizing abilities as well as tumor photobiological activities of Chlorin F methyl ether. Acta Pharmaceutica Sinica, 2000, 35(1): 63-66, 2001, 39(1): 1-4; Pandey, R. K., et al. Chlorin and porphyrin derivatives as potential photosensitizers in photodynamic therapy. Photochemistry and Photobiology, 1991, 53(1): 65-72). Although the potential effects of almost of optimized products are better, most of them have non-ideal activity data, higher toxicity, harder synthesis or lower yield. Thus, their use is hard to be achieved.
After 2000, some photosensitizers are successfully used in clinic, wherein verteporfiin comes into the market in 2000. Temoporfin comes into the market in 2001. Talaporfin comes into the market in 2004. In addition, phase I and II clinical test of pyropheophorbide a n-hexyl ether [HPPH, trade name: Photochlor] have been conducted by Hisun Pharmaceutical. It can be used for treating head and neck cancer. However, drugs for treating tumors are so less, patents have so little space to select them. Further, the treatment effects also need to be enhanced, and the toxicity might be reduced. Therefore, in the present application chlorin e6 is used as a raw material, its structure is modified and optimized to develop a new chlorins photosensitizer with a high effect and a low toxicity.